Muscarinic receptors are a G-protein coupled receptor (GPCR) family having five family members M1, M2, M3, M4 and M5. Of the five muscarinic subtypes, three (M1, M2 and M3) are known to exert physiological effects on human lung tissue.
Parasympathetic nerves are the main pathway for reflex bronchoconstriction in human airways and mediate airway tone by releasing acetylcholine onto muscarinic receptors Airway tone is increased in patients with respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), and for this reason muscarinic receptor antagonists have been developed for use in treating airway diseases. Muscarinic receptor antagonists often called anticholinergics in clinical practice, have gained widespread acceptance as a first-line therapy for individuals with COPD, and their use has been extensivley reviewed in the literature (e.g. Lee et al, Current Opinion in Pharmacology 2001, 1, 223-229).
When used to treat respiratory disorders, muscarinic receptor antagonists are typically administered by inhalation. However, when administered by inhalation a significant proportion of the muscarinic receptor antagonist is often absorbed into the systemic circulation resulting in reported side effects such as dry mouth. Additionally, the majority of muscarinic antagonists have a relatively short duration of action requiring that they be administered several times a day. Such a multiple-daily dosing regime is not only inconvenient to the patient but also creates a significant risk of inadequate treatment due to patient non-compliance associated with the frequent repeat dosing schedule.
There therefore remains a need for novel compounds that are capable of blocking muscarinic receptors. In particular, a need exists for new muscarinic antagonists that have high potency and reduced systemic side effects when administered by inhalation. Moreover, a need exists for new muscarinic antagonists that exhibit a long duration of action when dosed by inhalation, and which are amenable to either once or twice daily dosing.
WO 98/04517 describes arylcyclopropane, arylcyclobutane, arylcyclopentane and arylcyclohexane carboxylic esters having antimuscarinic activity on the urinary bladder smooth muscle.
Our co-pending application PCT/GB2007/004350 relates to compounds of formula (I)
wherein    R1 and R2 together with the carbon atom to which they are both directly attached form a 7 membered aliphatic carbocyclic ring which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-6 alkoxy, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2 and C1-6 alkyl which C1-6 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl;    R3 represents phenyl or a 5 to 6 membered heteroaryl ring, each of which may be optionally substituted by one or more substituents independently selected from halogen cyano, nitro, SH, S(O)0-2R9, NR10R11, S(O)2NR12R13, C(O)NR14R15, C(O)2R16, NR17S(O)2R18, NR19C(O)R20, NR21C(O)2R22, NR23C(O)NR24R25, OR26 and C1-6 alkyl which C1-6 alkyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-6 alkoxy, NH2, NH(C1-6 alkyl) and N(C1-6 alkyl)2;    R4 represents a group of formula (II) or (IIIa) or (IIIb);
wherein    Y is —CH2—, —CH2CH2— or —CH2CH2CH2— and the substitution on the ring in group (II) may be in the 3 or 4 positions;    a is 1 or 2;    b is 1 or 2;    Z is —CH2—;    R5 represents a group of formula (IV)
wherein    w is 0 or 1;    R6 represents C1-4 alkylene optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-6 alkoxy, NH2, NH(C1-6 alkyl) and N(C1-6 alkyl)2;    when w is 0, y is 0; when w is 1, y is 0 or 1;    Q represents O, S(O)0-2, NR8, —CONR8—, —SO2NR8—, —NR8CO—, —NR8SO2—, —OC(O)—, —C(O)O—, —HC═CH— or ethynylene;    R7 represents a cyclic group Cyc1 or a C1-4 alkyl group which C1-4 alkyl group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-4 alkoxy, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, a cyclic group Cyc2 and —OCyc2; and R7 may additionally represent hydrogen when Q represents O, NR8, —CONR8—, —SO2NR8—, —C(O)O—, —HC═CH— or ethynylene;    Cyc1 and Cyc2 each independently represent aryl, heteroaryl, a 3 to 8 membered aliphatic carbocyclic ring or a 4 to 8 membered aliphatic heterocyclic ring, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, nitro, SH, S(O)0-2R9, NR10R11, S(O)2NR12R13, C(O)NR14R15, C(O)2R16, NR17S(O)2R18, NR19C(O)R20, NR21C(O)2R22, NR23C(O)NR24R25, OR26, phenyl and C1-6 alkyl which phenyl or C1-6 alkyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-6 alkoxy, NH2, NH(C1-6 alkyl) and N(C1-6 alkyl)2;    R8 represents hydrogen or C1-6 alkyl;    R9 and R18 each independently represent C1-6 alkyl, which C1-6 alkyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-6 alkoxy, NH2, NH(C1-6 alkyl) and N(C1-6 alkyl)2; and    R10, R11, R12, R13, R14, R15, R16, R17, R19, R20, R21, R22, R23, R24, R25 and R26 each independently represent hydrogen or C1-6 alkyl, which C1-6 alkyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-6 alkoxy, NH2, NH(C1-6 alkyl) and N(C1-6 alkyl)2; or any of R10 and R11, R12 and R13, R14 and            R15 or R24 and R25, together with the nitrogen atom to which they are both attached, may form a 4 to 8 membered aliphatic heterocyclic ring, which heterocyclic ring may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl and C1-6 alkyl, which C1-6 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl;            and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.